Katsunori Kanazawa

Comparative Study on the Efficacy of Liposomal Amphotericin B and Voriconazole in a Murine Pulmonary Aspergillosis Model

Background:No clinical studies have compared the efficacy of liposomal formulation AMB (L-AMB) and voriconazole (VRC) in the treatment of pulmonary aspergillosis. The aim of this study was to compare the efficacy of L-AMB and VRC in murine pulmonary aspergillosis.Methods: Leucopenic mice were infected intratracheally with Aspergillus fumigatus and treated intravenously with L-AMB (once a day) or VRC (twice a day). Results: L-AMB and VRC at a dose of ≥5 and ≥20 mg/kg, respectively, significantly prolonged the survival time of infected mice and reduced the pulmonary fungal burden in comparison with the control group. At the maximum recommended dose for clinical use, 5 mg/kg of L-AMB exhibited greater efficacy than 10 mg/kg of VRC, which achieved an area under the concentration-time curve level equivalent to that of 6 mg/kg (loading dose) in humans, in terms of increasing survival and reducing the fungal burden. Conclusion: The in vivo efficacy of L-AMB was superior to that of VRC at the maximum recommended dose in a murine pulmonary aspergillosis model.

The Mode of Action of 2-(Thiazol-2-ylthio)-1β-methylcarbapenems against Pseudomonas aeruginosa : The Impact of Outer Membrane Permeability and the Contribution of MexAB-OprM Efflux System

The mode of action of a series of 2-(4-dihydropyrrolylthiazol-2-ylthio) and 2-(4-tetrahydropyridinylthiazol-2-ylthio)-1β-methylcarbapenem analogues against Pseudomonas aeruginosa was investigated with regard to contributions of the affinity for penicillin binding proteins (PBPs), the outer membrane permeability, and the effect of the MexAB-OprM efflux system. In this series of carbapenems, the introduction of a substituent in C-2 side chain with a change in physicochemical properties affected the antipseudomonal activity depending on the molecular weight. However, these structural modifications did not affect the affinity for pseudomonal PBPs significantly. It was confirmed that the affinity for PBPs was not an important determinant of the antipseudomonal activity of this series of carbapenems. OprD porin-deficiency did not affect antipseudomonal activity either. On the other hand, the MIC of these carbapenems against P. aeruginosa significantly decreased in the presence of outer membrane permeabilizer. This result strongly suggests that the cause of the relatively low antipseudomonal activity of these carbapanems is their low permeability through the outer membrane of P. aeruginosa. And also, in the presence of outer membrane permeabilizer, the MICs against MexAB-OprM deficient mutants remarkably decreased and were very close to the value of the IC50 for pseudomonal PBPs. From this result, it was clear that the effect of the MexAB-OprM efflux system was also an important determinant of antipseudomonal activity of these carbapenems. In conclusion, the major determinants of the antipseudomonal activity of the 2-(thiazol-2-ylthio)-1β-methylcarbapenems are the outer membrane permeability and the effect of the MexAB-OprM efflux system, not the affinity for pseudomonal PBPs.

Pharmacodynamics of SMP-601 (PTZ601) against Vancomycin-Resistant Enterococcus faecium and Methicillin-Resistant Staphylococcus aureus in Neutropenic Murine Thigh Infection Models

ABSTRACT SMP-601 (also known as PTZ601, PZ-601, or SM-216601) is a novel parenteral carbapenem with potent activity against multidrug-resistant gram-positive pathogens, including vancomycin-resistant Enterococcus faecium (VREF) and methicillin-resistant Staphylococcus aureus (MRSA). The pharmacodynamics of SMP-601 against VREF and MRSA were investigated in neutropenic murine thigh infection models. The percentage of the dosing interval that the unbound SMP-601 concentration exceeded the MIC (f%T>MIC) was the pharmacokinetic-pharmacodynamic parameter that correlated most closely with efficacy with R2 values of 0.81 to 0.84 for two strains of VREF and 0.92 to 0.93 for two strains of MRSA, whereas the R2 values for the area under the concentration-time curve from 0 to 24 h divided by the MIC were 0.12 to 0.89, and the R2 values for the peak level divided by the MIC were 0 to 0.22. The f%T>MIC levels required for static or killing efficacy against two strains of VREF (9 to 19%) apparently were lower than those against two strains of MRSA (23 to 37%). These results suggested that SMP-601 showed time-dependent in vivo efficacy against VREF and MRSA, and SMP-601 had a sufficient therapeutic effect against VREF infections at lower exposure conditions compared to those for with MRSA infections.

AmBisome: relationship between the pharmacokinetic characteristics acquired by liposomal formulation and safety/efficacy

Abstract Amphotericin B (AMPH-B) is a polyene antifungal agent with a superior and broad fungicidal spectrum, but its administration at a dose sufficient for treatment is difficult because of dose- and duration-dependent nephrotoxicity. To solve this dilemma, a liposomal formation of AMPH-B that achieved reduction of adverse effects while maintaining the efficacy, AmBisome® (L-AMB), was developed. In L-AMB, AMPH-B molecules are stabilized by phospholipids and cholesterol in the liposomal lipid bilayer, reducing the cytotoxicity for animal cells compared with that of the free-form AMPH-B. In addition, extravascular permeation of L-AMB is limited in normal tissue because of the liposome particle size (particle diameter: 100 nm or smaller), a high blood level is maintained and the distribution in organs, including the kidney is reduced, contributing to the improvement of the safety. On the other hand, vascular permeation increases due to inflammation and damage by fungal invasion, which increases L-AMB transfer from the circulation to lesions and its antifungal activity. Furthermore, since the parameter most closely correlated with the in vivo outcome of L-AMB is Cmax/MIC, the pharmacokinetic (PK) characteristics of L-AMB, which result in a high blood level than that for the free-form AMPH-B, is advantageous for antifungal activity. Incorporation of AMPH-B into the liposomal membrane resulted in PK characteristics of L-AMB markedly different from those of AMPH-B, and the superior efficacy and safety were achieved based on these characteristics. In this review, the relationship between the PK characteristics of L-AMB and safety/efficacy is introduced.

Influence of Fungicidal Activity against Candida tropicalis on the Efficacy of Micafungin and Liposomal Amphotericin B in a Neutropenic Murine Lethal Infection Model

Objectives: To investigate the correlation between in vitro killing activity and in vivo efficacy of micafungin (MCFG) and liposomal amphotericin B (L-AMB) against Candida tropicalis in a neutropenic murine lethal infection model. Methods:Candida albicans (one strain) and C. tropicalis (three strains) were tested in time-kill studies. Cyclophosphamide-treated mice were inoculated intravenously with each strain. One day after inoculation, antifungals were administered intravenously once daily for 1 or 3 days. Results: MCFG exhibited fungicidal activity against C. albicans ATCC 90029 and C. tropicalis SP-20142, and fungistatic activity against C. tropicalis ATCC 42678 and SP-20047. The ED50s (dosage that results in 50% survival) of MCFG for C. tropicalis ATCC 42678 and SP-20047 (4.1–50 mg/kg) were higher than those for other strains (1.6–12 mg/kg). A 1-day course of MCFG was not effective against C. tropicalis ATCC 42678 and SP-20047 at the clinical dose (5 mg/kg), which achieved an AUC level almost equal to that of 100 mg in humans, whereas a 3-day course of 5 mg/kg MCFG was efficacious against all strains. In contrast, L-AMB showed fungicidal activity against all strains tested and the ED50s of L-AMB were 0.08–0.65 mg/kg. In both treatment regimens, the minimum effective doses of L-AMB (≤0.5 mg/kg) were less than the clinical dosage (≤5 mg/kg). Conclusions: The in vivo efficacy of MCFG and L-AMB showed a correlation with the in vitro killing activity. At the clinical dose, L-AMB exerted anti-C. tropicalis activity within a shorter treatment period than MCFG.